Cooper, Nectaroula; (2007) Design, synthesis and evaluation of novel C2-aryl pyrrolobenzodiazepines as potential anticancer agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The pyrrolobenzodiazepines are a family of anti-tumour antibiotics discovered in the fermentation broths of various streptomyces species. Whilst the early naturally occurring PBDs showed promise in vitro many were found to lack efficacy or give rise to cardiotoxicity in vivo. Many potent naturally occurring PBDs possess a C-ring associated endo-exo unsaturation motif coupled with the 9-hydroxyl group linked to in vivo cardiotoxicity. In this project a set of novel, totally synthetic PBDs that retain the endo-exo unsaturation motif, in the form of a C2-aryl substituent, but which lack the 9-hydroxy group have been designed and synthesised in an attempt to provide potent non cardiotoxic PBDs for biological; evaluation. The C2-aryl substituents were successfully introduced by the Suzuki coupling or aryl boronic acids to the enol triflate derivative of an N10 protected PBD-dilactam. Reduction and simultaneous deprotection of the C2-aryl dilactams afforded the novel C2-aryl PBDs. The Suzuki coupling reactions could be conveniently carried out in parallel, using a carousel reactor, allowing the preparation of a small C2-aryl PBD library. The novel C2-aryl compounds underwent biological evaluation at both the Institute for Experimental Oncology, Germany and the National Cancer Institute of the U.S.A. The C2-aryl compounds were found to possess nanomolar activity in cancer cell lines. The NCI study revealed that the molecules possessed preferential activity against melanoma and renal panels in particular. A number of C2-aryl compounds were selected for in vivo testing based on the encouraging cytotoxicity data. The molecules exhibited some evidence of in vivo activity, with the 2,6-dimethyl analogue showing unexpected in vivo activity. In vivo testing of the naphthyl analogue, which performed well in both cytotoxicity assays and biophysical studies is awaited with interest. Finally pilot studies were undertaken to investigate the feasibility of applying the Suzuki synthetic strategy to the synthesis of C2-aryl PBD dimers.

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